EP3297692A1 - Surgical adhesives - Google Patents

Surgical adhesives

Info

Publication number
EP3297692A1
EP3297692A1 EP16732691.7A EP16732691A EP3297692A1 EP 3297692 A1 EP3297692 A1 EP 3297692A1 EP 16732691 A EP16732691 A EP 16732691A EP 3297692 A1 EP3297692 A1 EP 3297692A1
Authority
EP
European Patent Office
Prior art keywords
methacrylate
composition according
acrylate
biological tissue
monomer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP16732691.7A
Other languages
German (de)
French (fr)
Other versions
EP3297692B1 (en
Inventor
Christophe Derail
Laetitia BADIE
Eric Papon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cohesives
Centre National de la Recherche Scientifique CNRS
Universite de Bordeaux
Institut Polytechnique de Bordeaux
Universite de Pau et des Pays de lAdour
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Bordeaux
Institut Polytechnique de Bordeaux
Universite de Pau et des Pays de lAdour
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Universite de Bordeaux, Institut Polytechnique de Bordeaux, Universite de Pau et des Pays de lAdour filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP3297692A1 publication Critical patent/EP3297692A1/en
Application granted granted Critical
Publication of EP3297692B1 publication Critical patent/EP3297692B1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A61B2017/005—Surgical glue applicators hardenable using external energy source, e.g. laser, ultrasound

Definitions

  • the present invention belongs to the field of surgical glues, more particularly the present invention relates to compositions for use in a method for adhesion of biological tissue to one another, for adhesion of a material to a biological tissue, for the adhesion of an adhesive or substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for strengthening a biological tissue and / or for fixing and stabilizing a biological tissue .
  • surgical glues have very low adhesive properties and therefore can not be used as an adhesive or as a surgical suture.
  • the application of surgical glues is most of the time directly on the fabric, without preparation of the bonding surface.
  • the penetration into the tissues is weak or non-existent, which leads to poor quality bonding.
  • Applicants have found that current glues do not stick or penetrate the tissues. As a result, they have developed a glue capable of penetrating deep into the area of the biological tissue in order to anchor the glue in the fabric.
  • document EP1994886A1 discloses a surgical glue comprising polymerizable monomers of the cyanoacrylate family.
  • the polymerization of the latter is triggered by the moisture of the biological tissue as soon as contact is made between the surgical glue and the latter. Therefore, despite the low viscosity of this surgical glue, the polymerization of the cyanoacrylate monomers takes place on the surface of the biological tissue. Thus, the cyanoacrylate monomers can not penetrate the biological tissue. The cyanoacrylate monomers can not be anchored in the tissue, which explains the low mechanical strength and low clinical efficacy of cyanoacrylate surgical glues.
  • the present invention proposes to provide a new type of surgical glues.
  • the compositions and the process according to the invention make it possible to obtain an effective and resistant bonding.
  • the breakage of the bonding is done by the propagation of a crack in the bonded fabric or in the glue joint and not at the glue-fabric interface. Bonding is applicable to all types of biological tissues (soft tissues, bones). Such bonding also makes it possible to obtain effective haemostasis or aerostasis. It also allows to replace the surgical suture by a collage.
  • the principle of the invention is to allow a polymerizable monomer to penetrate into the biological tissue to allow anchoring of the polymer in the tissue thereby enhancing the adhesion properties to the tissue surface.
  • the present invention relates to a composition for use in a process for the adhesion of between them, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or a substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for reinforcing a biological tissue and / or for fixing and stabilizing a biological tissue, characterized in that it comprises a polymerizable monomer under the effect of ultraviolet (UV) radiation and in that its viscosity is less than 10 mPa.s at 20 ° C.
  • UV ultraviolet
  • the present invention also relates to a composition for use in a method for adhesion of biological tissues to one another, for adhesion of a material to a biological tissue, for adhesion of an adhesive or substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for reinforcing a biological tissue and / or for fixing and stabilizing biological tissue, which is remarkable in that it comprises a polymerizable monomer under effect of ultraviolet (UV) radiation and that its viscosity is less than 10 mPa.s at 20 ° C.
  • UV ultraviolet
  • the viscosity of the composition may in particular be measured by a falling ball viscometer according to DIN53015.
  • the term "polymerizable monomer” means a monomer whose polymerization can be initiated under the effect of ultraviolet (UV) radiation.
  • UV radiation ultraviolet
  • the polymerization of the composition according to the invention can be initiated only by ultraviolet radiation to the exclusion of any other mode of initiation.
  • the initiation of the polymerization of the polymerizable monomers consists of irradiation by UV radiation.
  • said UV radiation has a wavelength of between 150 nm to 280 nm, even more preferably between 170 nm to 260 nm and quite preferably between 190 nm and 240 nm.
  • said UV radiation has a wavelength of between 200 nm and 400 nm, even more preferably between 300 nm and 400 nm and quite preferably between 350 nm and 400 nm.
  • the polymer obtained after polymerization of the monomer is preferably a biocompatible polymer.
  • composition according to the invention does not comprise polymerizable monomers whose polymerization can be initiated at the single contact of water molecules. This avoids the instantaneous polymerization of the composition according to the invention in contact with the tissues.
  • composition according to the invention does not comprise polymerizable monomers of the family of cyanoacrylates known to polymerize rapidly in contact with water and / or ambient humidity.
  • the polymerizable monomer is only polymerizable by irradiation with UV radiation.
  • said viscosity is less than 6 mPa.s at 20 ° C. According to an even more preferred embodiment, said viscosity is less than 4 mPa.s at 20 ° C.
  • said viscosity is less than 2 mPa.s at 20 ° C and more particularly between 1 and 2 mPa.s at 20 ° C.
  • the composition according to the invention is not a hydrogel.
  • said monomer is a methacrylate acrylate monomer or an acrylate or methacrylate oligomer.
  • said monomer comprises a polar function.
  • polar function refers to a group of atoms in which the electrons are distributed asymmetrically, thus allowing this polar function to participate in electrostatic interactions.
  • Said polar function can in particular be chosen from the group comprising the hydroxyl, amide, carboxyl, amino, carbonate, carbamate, sulfonamide, sulfonic, phosphonic, methoxyethyl, methoxyethoxyethyl, hydroxyethyl and hydroxyethoxyethyl functions.
  • said acrylate monomer is selected from the group consisting of mono-, di-, tri-, tetra- and penta-acrylate or methacrylate, and mixtures thereof.
  • said acrylate monomer is chosen from the group comprising acrylic acid and methyl methacrylate; dimethylaminoethyl methacrylate; ethyl acrylate; cyclohexyl methacrylate; 2-hydroxyethyl methacrylate; 3-hydroxypropyl acrylate; alpha-bromoethyl acrylate; alpha-chloroethyl acrylate; the chloromethyl methacrylate; 2-bromoethyl methacrylate; 2-naphthyl methacrylate; paratolyl acrylate; parachlorophenyl methacrylate; metabromophenyl acrylate; 2,4,6-tribromophenyl acrylate; parachlorobenzyl methacrylate; metamethoxybenzyl methacrylate; paraethylbenzyl acrylate; 1,6-hexanediol di methacrylate; neopentyl glyco
  • said acrylate monomer is chosen from the group 1 'hydroxyethyl) methacrylate, acrylic acid,
  • said acrylate monomer is chosen from the group comprising acrylic acid, 1 '(hydroxyethyl) methacrylate,
  • said acrylate monomer is selected from the group consisting of acrylic acid, tert-butyl acrylate and mixtures thereof. According to another most preferred embodiment, said acrylate monomer is selected from the group consisting of acrylic acid, dimethylaminoethyl methacrylate and mixtures thereof.
  • said monomer has a molar mass of between 50 and 300 g. mol -1 .
  • said monomer has a concentration of between 90 and 100% by weight relative to the total mass of the composition.
  • said composition further comprises a reticulating agent.
  • said composition comprises only said monomer or said monomer and a retaining agent.
  • said crosslinking agent comprises an acrylate function.
  • said crosslinking agent is chosen from the group comprising multi-functional acrylates including in particular 1,6-hexanediol di acrylate, trimethylolpropane tri acrylate, 1,2-ethylene glycol di acrylate, pentaerythritol tetracrylate and mixtures thereof.
  • said crosslinking agent is chosen from the group comprising multi-functional acrylates including hexanediol dimethylacrylate (HDDMA), ethylene glycol dimethylacrylate (EGDMA), butanediol diacrylate (BDDA) ,, poly (ethylene glycol) diacrylate (PEGDA) and mixtures thereof.
  • HDDMA hexanediol dimethylacrylate
  • ELDMA ethylene glycol dimethylacrylate
  • BDDA butanediol diacrylate
  • PEGDA poly (ethylene glycol) diacrylate
  • said crosslinking agent is present at a concentration of between 1% and 5% by weight, even more preferably between 1 and 3% by weight, still more preferably between 1 and 2% by weight relative to the total mass of the composition.
  • said crosslinking agent is present at a concentration of between 0.1 and 3% by weight, even more preferably between 0.1 and 0.5% by weight, still more preferably between 0.1 and 0.3% by weight and quite preferably at a concentration of 0.2% by weight relative to the total mass of the composition.
  • the composition according to the invention comprises a photoinitiator.
  • a photoinitiator The skilled person will choose according to the emission spectrum of the lamp used the most suitable photoinitiator.
  • the photoinitiator may be chosen from: 2,2-dimethoxyphenyl-2-acetophenone (DMPA) camphorquinone or 4,4'-bis (diethylamino) enzophenone, this list being non-limiting.
  • DMPA 2,2-dimethoxyphenyl-2-acetophenone
  • 4,4'-bis (diethylamino) enzophenone this list being non-limiting.
  • the photoinitiator is used at a concentration of between 0.2 and 1%, preferably between 0.2 and 0.3% by weight.
  • said light ⁇ initiator is DMPA.
  • said composition comprises a solvent and even more preferably said solvent is water.
  • said solvent is an alcohol and quite preferably ethanol.
  • said composition is devoid of solvent.
  • compositions means that the composition according to the invention includes the elements mentioned.
  • present invention relates to compositions comprising only the elements cited to the exclusion of any other.
  • the present invention also relates to a method for the adhesion of biological tissues to one another, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or a substance to the surface of a tissue.
  • biological for closing an orifice (hemostasis, aerostasis) in a biological tissue, for strengthening a biological tissue and / or for setting and stabilizing a biological tissue, remarkable in that it comprises the steps:
  • the method according to the invention is advantageously non-invasive.
  • non-invasive means that the method according to the invention does not include any surgical step of accessing the tissue to be treated.
  • the method according to the invention is implemented on a biological tissue directly accessible (e.g. the skin) or previously made accessible by other methods.
  • the characteristics of the UV radiation used are adapted to the constituents of the composition, in particular to the nature of the polymerizable monomer and to its concentration in the composition.
  • said method further comprises after step (iii), a step (iv) of apposition of a synthetic fabric to the surface of the fabric.
  • said UV radiation has a wavelength of between 150 and 280 nm. According to a preferred embodiment, said UV radiation has a power of between 100 and 200 W.
  • the present invention also relates to a set of parts comprising a composition according to the invention and a source of UV radiation.
  • the UV radiation source of the set of parts can emit UV radiation suitable for polymerizing and / or aiding the polymerization and / or accelerating the polymerization of the polymerizable monomer of the composition.
  • UV radiation source refers to any artificial means capable of producing UV radiation and more particularly a radiation of wavelength lying in the range 150 nm to 280 nm, even more preferably in the range 170 nm to 260 nm and most preferably in the range 190 nm to 260 nm. nm and 240 nm.
  • said UV radiation is of power between 0.5 W and 200W and quite preferentially between 100 and 200W.
  • UV radiation source refers to any artificial means capable of producing UV radiation with a wavelength of between 200 nm and 400 nm, and even more preferably between 300 nm at 400 nm and quite preferably between 350 nm and 400 nm.
  • said UV radiation has a wavelength of between 150 and 280 nm and a power of between 100 and 200 W.
  • Acrylic / (Hydroxyethyl) methacrylate / crosslinking agents, or acrylic acid / dimethylaminoethyl methacrylate / crosslinking agents of viscosity and varying concentrations were deposited on bovine pericardial samples. This step is carried out at 20 ° C. These pericardial samples were subjected to 150 W UV radiation for a period of 5 minutes to initiate polymerization of the monomers. The radiation source was placed 10 cm from the pericardium.
  • the pericardial samples were subjected to UV radiation under conditions identical to those of the previous step.
  • a peel test was then performed by pulling 180 ° on the fiberglass strip in a controlled oven at 37 ° C.
  • the rest time of the belt installed between the jaws of the traction machine is one minute, the temperature within the sample is, at the time of the test start, 30 ° C + or - 4 ° C.
  • a solution of acrylic acid was deposited on pericardial samples. Said pericardial samples were subjected to 150 W UV radiation for 5 min., to trigger the polymerization of the monomers. The radiation source was placed 10 cm from the pericardium.
  • the pericardial samples were then cut transversely and observed by scanning electron microscopy.
  • breaking strength i.e. the resistance of the bonding
  • compositions used All Viscosity [mPa.s] Resistance to rupture F / b the compositions comprise [N / m] in the pericardium 0.25% by weight of DMPA)
  • the presence of the formed polymer infiltrated in the surface of the fabric is observed at a depth of 50 ⁇ m. It is furthermore observed that the polymer formed has penetrated into the spaces between the collagen fibers of the tissues.

Abstract

The present invention belongs to the field of surgical adhesives; more particularly, the present invention relates to compositions for the adhesion of biological tissues to one another, for the adhesion of a biological tissue to a material, for the adhesion of an adhesive or of a substance to the surface of a biological tissue, for blocking an orifice (haemostasis, aerostasis) in a biological tissue, for reinforcing a biological tissue and/or for fixing and stabilising a biological tissue. The present invention relates in particular to a composition for the adhesion of biological tissues to one another, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or of a substance to the surface of a biological tissue, for blocking an orifice in a biological tissue, for reinforcing a biological tissue and/or for fixing and stabilising a biological tissue, characterized in that it comprises a monomer that is polymerisable under the effect of ultraviolet (UV) radiation and in that the viscosity of said composition is less than 10 mPa.s at 20°C.

Description

COLLES CHIRURGICALES  SURGICAL GLUES
Domaine technique Technical area
La présente invention appartient au domaine des colles chirurgicales, plus particulièrement la présente invention concerne des compositions destinées à être utilisées dans un procédé pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un matériau à un tissu biologique, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice (hémostase, aérostase) dans un tissu biologique, pour renforcer un tissu biologique et/ou, pour fixer et stabiliser un tissu biologique. The present invention belongs to the field of surgical glues, more particularly the present invention relates to compositions for use in a method for adhesion of biological tissue to one another, for adhesion of a material to a biological tissue, for the adhesion of an adhesive or substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for strengthening a biological tissue and / or for fixing and stabilizing a biological tissue .
Technique antérieure Prior art
Un certain nombre de techniques chirurgicales mettent en œuvre des colles chirurgicales. Ces dernières sont principalement utilisées pour aider à obtenir une hémostase chirurgicale. Toutefois, l'efficacité des colles chirurgicales dans cette indication est controversée et d'autres utilisations comme pour l' aérostase ne montrent pas de meilleurs résultats. A number of surgical techniques implement surgical glues. These are mainly used to help achieve surgical hemostasis. However, the effectiveness of surgical glues in this indication is controversial and other uses such as for aerostasis show no better results.
Par ailleurs, les colles chirurgicales ont de très faibles propriétés adhésives et ne peuvent donc pas être utilisées en tant qu'adhésif ni comme suture chirurgicale. L'application des colles chirurgicales se fait la plupart du temps directement sur le tissu, sans préparation de la surface de collage. La pénétration dans les tissus est faible ou inexistante ce qui entraine un collage de mauvaise qualité. Les déposants ont constaté que les colles actuelles ne collent pas et ne pénètrent pas dans les tissus. En conséquence, ils ont mis au point une colle apte à pénétrer en profondeur dans la superficie du tissu biologique afin de réaliser un ancrage de la colle dans le tissu. In addition, surgical glues have very low adhesive properties and therefore can not be used as an adhesive or as a surgical suture. The application of surgical glues is most of the time directly on the fabric, without preparation of the bonding surface. The penetration into the tissues is weak or non-existent, which leads to poor quality bonding. Applicants have found that current glues do not stick or penetrate the tissues. As a result, they have developed a glue capable of penetrating deep into the area of the biological tissue in order to anchor the glue in the fabric.
Par exemple, on connaît du document EP1994886A1, une colle chirurgicale comprenant des monomères polymérisables de la famille des cyanoacrylates . La polymérisation de ces derniers est déclenchée par l'humidité du tissu biologique dès que le contact se fait entre la colle chirurgicale et celui-ci. En conséquence, malgré la faible viscosité de cette colle chirurgicale, la polymérisation des monomères de cyanoacrylate a lieu à la surface du tissu biologique. Ainsi, les monomères de cyanoacrylates ne peuvent pas pénétrer dans le tissu biologique. Les monomères de cyanoacrylate ne peuvent pas s'ancrer dans le tissu ce qui explique la faible résistance mécanique et la faible efficacité clinique des colles chirurgicales à base de cyanoacrylate.  For example, document EP1994886A1 discloses a surgical glue comprising polymerizable monomers of the cyanoacrylate family. The polymerization of the latter is triggered by the moisture of the biological tissue as soon as contact is made between the surgical glue and the latter. Therefore, despite the low viscosity of this surgical glue, the polymerization of the cyanoacrylate monomers takes place on the surface of the biological tissue. Thus, the cyanoacrylate monomers can not penetrate the biological tissue. The cyanoacrylate monomers can not be anchored in the tissue, which explains the low mechanical strength and low clinical efficacy of cyanoacrylate surgical glues.
Ainsi la présente invention se propose de fournir un nouveau type de colles chirurgicales. Les compositions et le procédé selon l'invention permettent d'obtenir un collage efficace et résistant. La rupture du collage se fait par la propagation d'une fissure dans le tissu collé ou dans le joint de colle et non à l'interface colle-tissu. Le collage est applicable à tout type de tissus biologiques (tissus mous, os) . Un tel collage permet par ailleurs d'obtenir une hémostase ou une aérostase efficace. Il permet également de remplacer la suture chirurgicale par un collage.  Thus the present invention proposes to provide a new type of surgical glues. The compositions and the process according to the invention make it possible to obtain an effective and resistant bonding. The breakage of the bonding is done by the propagation of a crack in the bonded fabric or in the glue joint and not at the glue-fabric interface. Bonding is applicable to all types of biological tissues (soft tissues, bones). Such bonding also makes it possible to obtain effective haemostasis or aerostasis. It also allows to replace the surgical suture by a collage.
Résumé de l'invention Summary of the invention
Le principe de l'invention consiste à laisser pénétrer un monomère polymérisable dans le tissu biologique afin de permettre un ancrage du polymère dans le tissu, ce qui renforce les propriétés d'adhésion à la surface du tissu.  The principle of the invention is to allow a polymerizable monomer to penetrate into the biological tissue to allow anchoring of the polymer in the tissue thereby enhancing the adhesion properties to the tissue surface.
Ainsi, la présente invention concerne une composition destinée à être utilisée dans un procédé pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un matériau à un tissu biologique, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice (hémostase, aérostase) dans un tissu biologique, pour renforcer un tissu biologique et/ou pour fixer et stabiliser un tissu biologique, remarquable en ce qu'elle comprend un monomère polymérisable sous l'effet d'un rayonnement ultra-violet (UV) et en ce que sa viscosité est inférieure à 10 mPa.s à 20°C. Thus, the present invention relates to a composition for use in a process for the adhesion of between them, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or a substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for reinforcing a biological tissue and / or for fixing and stabilizing a biological tissue, characterized in that it comprises a polymerizable monomer under the effect of ultraviolet (UV) radiation and in that its viscosity is less than 10 mPa.s at 20 ° C.
La présente invention concerne également une composition pour une utilisation dans un procédé pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un matériau à un tissu biologique, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice (hémostase, aérostase) dans un tissu biologique, pour renforcer un tissu biologique et/ou pour fixer et stabiliser un tissu biologique, remarquable en ce qu'elle comprend un monomère polymérisable sous l'effet d'un rayonnement ultra-violet (UV) et en ce que sa viscosité est inférieure à 10 mPa.s à 20°C.  The present invention also relates to a composition for use in a method for adhesion of biological tissues to one another, for adhesion of a material to a biological tissue, for adhesion of an adhesive or substance to the surface of a biological tissue, for sealing an orifice (hemostasis, aerostasis) in a biological tissue, for reinforcing a biological tissue and / or for fixing and stabilizing biological tissue, which is remarkable in that it comprises a polymerizable monomer under effect of ultraviolet (UV) radiation and that its viscosity is less than 10 mPa.s at 20 ° C.
La viscosité de la composition peut notamment être mesurée par un viscosimètre à chute de bille selon la norme DIN53015. The viscosity of the composition may in particular be measured by a falling ball viscometer according to DIN53015.
En effet, les déposants ont pu mettre en évidence que la viscosité de ladite composition permettait d'obtenir une pénétration importante dans les tissus biologiques et une adhésion optimale.  Indeed, the applicants have been able to demonstrate that the viscosity of said composition allowed to obtain a significant penetration into the biological tissues and optimal adhesion.
Dans le cadre de la présente invention le terme « monomère polymérisable » entend désigner un monomère dont la polymérisation peut être initiée sous l'effet d'un rayonnement ultra-violet (UV) . Ce mode d'initiation de la polymérisation permet d'attendre que la composition de monomères ait pénétré dans les tissus avant de déclencher la polymérisation. Préfèrentiellement , la polymérisation de la composition selon l'invention ne peut être initiée que par les rayonnements ultra-violet à l'exclusion de tout autre mode d'initiation. En particulier, l'initiation de la polymérisation des monomères polymérisables consiste en l'irradiation par rayonnements UV. De manière préférée, ledit rayonnement UV a une longueur d'onde comprise entre de 150 nm à 280 nm, encore plus préfèrentiellement entre 170 nm à 260 nm et tout à fait préfèrentiellement entre 190 nm et 240 nm. In the context of the present invention the term "polymerizable monomer" means a monomer whose polymerization can be initiated under the effect of ultraviolet (UV) radiation. This mode of initiation of the polymerization makes it possible to wait for the composition of The monomers penetrated the tissues before initiating the polymerization. Preferably, the polymerization of the composition according to the invention can be initiated only by ultraviolet radiation to the exclusion of any other mode of initiation. In particular, the initiation of the polymerization of the polymerizable monomers consists of irradiation by UV radiation. Preferably, said UV radiation has a wavelength of between 150 nm to 280 nm, even more preferably between 170 nm to 260 nm and quite preferably between 190 nm and 240 nm.
Selon un autre mode de réalisation préféré ledit rayonnement UV a une longueur d'onde comprise entre de 200 nm à 400 nm, encore plus préfèrentiellement entre 300 nm à 400 nm et tout à fait préfèrentiellement entre 350 nm et 400 nm.  According to another preferred embodiment, said UV radiation has a wavelength of between 200 nm and 400 nm, even more preferably between 300 nm and 400 nm and quite preferably between 350 nm and 400 nm.
Le polymère obtenu après polymérisation du monomère est préfèrentiellement un polymère biocompatible. The polymer obtained after polymerization of the monomer is preferably a biocompatible polymer.
Pour ces raisons, la composition selon l'invention ne comprend pas de monomères polymérisables dont la polymérisation peut être initiée au seul contact de molécules d'eau. On évite ainsi la polymérisation instantanée de la composition selon l'invention au contact des tissus.  For these reasons, the composition according to the invention does not comprise polymerizable monomers whose polymerization can be initiated at the single contact of water molecules. This avoids the instantaneous polymerization of the composition according to the invention in contact with the tissues.
Pour ces mêmes raisons, la composition selon l'invention ne comprend pas de monomères polymérisables de la famille des cyanoacrylates connues pour polymériser rapidement au contact de l'eau et/ou de l'humidité ambiante.  For these same reasons, the composition according to the invention does not comprise polymerizable monomers of the family of cyanoacrylates known to polymerize rapidly in contact with water and / or ambient humidity.
Préfèrentiellement , le monomère polymérisable est uniquement polymérisable par irradiation par rayonnements UV.  Preferably, the polymerizable monomer is only polymerizable by irradiation with UV radiation.
Selon un mode de réalisation préféré, ladite viscosité est inférieure à 6 mPa.s à 20°C. Selon un mode de réalisation encore plus préféré, ladite viscosité est inférieure à 4 mPa.s à 20°C. According to a preferred embodiment, said viscosity is less than 6 mPa.s at 20 ° C. According to an even more preferred embodiment, said viscosity is less than 4 mPa.s at 20 ° C.
Selon un mode de réalisation tout à fait préféré, ladite viscosité est inférieure à 2 mPa.s à 20°C et plus particulièrement entre 1 et 2 mPa.s à 20°C.  According to a most preferred embodiment, said viscosity is less than 2 mPa.s at 20 ° C and more particularly between 1 and 2 mPa.s at 20 ° C.
Selon un mode de réalisation préféré, la composition selon l'invention n'est pas un hydrogel.  According to a preferred embodiment, the composition according to the invention is not a hydrogel.
Selon un mode de réalisation préféré, ledit monomère est un monomère d'acrylate de méthacrylate ou un oligomère d'acrylate ou de méthacrylate.  According to a preferred embodiment, said monomer is a methacrylate acrylate monomer or an acrylate or methacrylate oligomer.
Selon un mode de réalisation préféré, ledit monomère comprend une fonction polaire.  According to a preferred embodiment, said monomer comprises a polar function.
Dans le cadre de la présente invention, le terme « fonction polaire » fait référence à un groupe d'atomes dans lequel les électrons sont répartis de façon asymétrique, permettant ainsi à cette fonction polaire de prendre part à des interactions électrostatiques. Ladite fonction polaire peut notamment être choisie dans le groupe comprenant les fonctions hydroxyle, amide, carboxyle, amino, carbonate, carbamate, sulfonamide, sulfonique, phosphonique, méthoxyéthyle, méthoxyéthoxyéthyle, hydroxyéthyle et hydroxyéthoxyéthyle .  In the context of the present invention, the term "polar function" refers to a group of atoms in which the electrons are distributed asymmetrically, thus allowing this polar function to participate in electrostatic interactions. Said polar function can in particular be chosen from the group comprising the hydroxyl, amide, carboxyl, amino, carbonate, carbamate, sulfonamide, sulfonic, phosphonic, methoxyethyl, methoxyethoxyethyl, hydroxyethyl and hydroxyethoxyethyl functions.
Selon un mode de réalisation préféré, ledit monomère d'acrylate est choisi dans le groupe comprenant les mono-, di-, tri-, tetra- et penta-acrylate ou méthacrylate, et leurs mélanges .  According to a preferred embodiment, said acrylate monomer is selected from the group consisting of mono-, di-, tri-, tetra- and penta-acrylate or methacrylate, and mixtures thereof.
Selon un mode de réalisation préféré, ledit monomère d'acrylate est choisi dans le groupe comprenant l'acide acrylique, le méthacrylate de méthyle; le méthacrylate de diméthylaminoéthyle ; l'acrylate d'éthyle; le méthacrylate de cyclohexyle ; le méthacrylate de 2-hydroxyethyle ; l'acrylate de 3-hydroxypropyle ; l'acrylate d'alpha- bromoéthyle ; l'acrylate d ' alpha-chloroéthyle ; le méthacrylate de chlorométhyle ; le méthacrylate de 2- bromoéthyle ; le méthacrylate de 2-naphtyle; l'acrylate de paratolyle; le méthacrylate de parachlorophényle ; l'acrylate de metabromophényle ; l'acrylate de 2 , 4 , 6-tribromophényle ; le méthacrylate de parachlorobenzyle ; le méthacrylate de metaméthoxybenzyle ; l'acrylate de paraéthylbenzyle ; le di méthacrylate de 1 , 6-hexanediol ; le di acrylate de neopentylglycol; le di méthacrylate de thiodiéthylène-glycol ; le di acrylate de bisphénol A éthoxyle; le di méthacrylate de bisphénol A éthoxyle; le triacrylate de pentaérythritol ; le triacrylate de glycéryle; le pentaacrylate de dipentaérythritol ; le triacrylate de triméthylolpropane ; le tri méthacrylate de 1 ' isocyanurate de tris ( 2-hydroxyéthyle ) ; le triacrylate de triméthylolpropane polyoxyéthylène ; un acrylate d'uréthane; un methacrylate d'uréthane; le sulfure de bis ( 4-methacryloylthiophényle ) ; l'acrylate de tert- butyle ; un éthylèneglycol ou un polyéthylèneglycol choisi dans le groupe constitué par l'acrylate, le methacrylate; le diacrylate, le dimethacrylate, et leurs mélanges. According to a preferred embodiment, said acrylate monomer is chosen from the group comprising acrylic acid and methyl methacrylate; dimethylaminoethyl methacrylate; ethyl acrylate; cyclohexyl methacrylate; 2-hydroxyethyl methacrylate; 3-hydroxypropyl acrylate; alpha-bromoethyl acrylate; alpha-chloroethyl acrylate; the chloromethyl methacrylate; 2-bromoethyl methacrylate; 2-naphthyl methacrylate; paratolyl acrylate; parachlorophenyl methacrylate; metabromophenyl acrylate; 2,4,6-tribromophenyl acrylate; parachlorobenzyl methacrylate; metamethoxybenzyl methacrylate; paraethylbenzyl acrylate; 1,6-hexanediol di methacrylate; neopentyl glycol diacrylate; thiodiethylene glycol di methacrylate; ethoxylated bisphenol A diacrylate; ethoxylated bisphenol A di methacrylate; pentaerythritol triacrylate; glyceryl triacrylate; dipentaerythritol pentaacrylate; trimethylolpropane triacrylate; tri-methacrylate of tris (2-hydroxyethyl) isocyanurate; trimethylolpropane triacrylate polyoxyethylene; a urethane acrylate; urethane methacrylate; bis (4-methacryloylthiophenyl) sulfide; tert-butyl acrylate; an ethylene glycol or a polyethylene glycol selected from the group consisting of acrylate, methacrylate; diacrylate, dimethacrylate, and mixtures thereof.
Selon un mode de réalisation tout à fait préféré, ledit monomère d'acrylate est choisi dans le groupe 1 ' Hydroxyéthyl ) methacrylate, l'acide acrylique, According to a most preferred embodiment, said acrylate monomer is chosen from the group 1 'hydroxyethyl) methacrylate, acrylic acid,
1 'Hydroxy (propyl) methacrylate, l'acrylate de tert-butyle, le méthacrylate de diméthylaminoéthyle et leurs mélanges. Hydroxy (propyl) methacrylate, tert-butyl acrylate, dimethylaminoethyl methacrylate and mixtures thereof.
Selon un mode de réalisation tout à fait préféré, ledit monomère d'acrylate est choisi dans le groupe comprenant l'acide acrylique, 1 ' (Hydroxyéthyl ) methacrylate,According to a most preferred embodiment, said acrylate monomer is chosen from the group comprising acrylic acid, 1 '(hydroxyethyl) methacrylate,
1 ' (Hydroxypropyl ) methacrylate et leurs mélanges. (Hydroxypropyl) methacrylate and mixtures thereof.
Selon un autre mode de réalisation tout à fait préféré, ledit monomère d'acrylate est choisi dans le groupe comprenant l'acide acrylique, l'acrylate de tert-butyle et leurs mélanges. Selon un autre mode de réalisation tout à fait préféré, ledit monomère d'acrylate est choisi dans le groupe comprenant l'acide acrylique, le méthacrylate de diméthylaminoéthyle et leurs mélanges. According to another most preferred embodiment, said acrylate monomer is selected from the group consisting of acrylic acid, tert-butyl acrylate and mixtures thereof. According to another most preferred embodiment, said acrylate monomer is selected from the group consisting of acrylic acid, dimethylaminoethyl methacrylate and mixtures thereof.
Selon un mode de réalisation préféré, ledit monomère a une masse molaire comprise entre 50 et 300g. mol-1. According to a preferred embodiment, said monomer has a molar mass of between 50 and 300 g. mol -1 .
Selon un mode de réalisation préféré, ledit monomère a une concentration comprise entre 90 et 100% en masse par rapport à la masse totale de la composition.  According to a preferred embodiment, said monomer has a concentration of between 90 and 100% by weight relative to the total mass of the composition.
Selon un mode de réalisation préféré, ladite composition comprend en outre un agent de rét iculat ion .  According to a preferred embodiment, said composition further comprises a reticulating agent.
Selon un mode de réalisation préféré, ladite composition ne comprend que ledit monomère ou que ledit monomère et un agent de rét iculat ion .  According to a preferred embodiment, said composition comprises only said monomer or said monomer and a retaining agent.
L'homme du métier est apte à choisir l'agent de réticulation le plus adapté en fonction du monomère utilisé.  Those skilled in the art are able to choose the most suitable crosslinking agent according to the monomer used.
Selon un mode de réalisation préféré, ledit agent de réticulation comprend une fonction acrylate.  According to a preferred embodiment, said crosslinking agent comprises an acrylate function.
Selon un mode de réalisation préféré, ledit agent de réticulation est choisi dans le groupe comprenant les acrylates mult i-fonct ionnels comprenant notamment le 1,6- hexanediol di acrylate, le triméthylolpropane tri acrylate, le 1,2-éthylène glycol di acrylate, le pentaérythritol tétracrylate et les mélanges de ceux-ci.  According to a preferred embodiment, said crosslinking agent is chosen from the group comprising multi-functional acrylates including in particular 1,6-hexanediol di acrylate, trimethylolpropane tri acrylate, 1,2-ethylene glycol di acrylate, pentaerythritol tetracrylate and mixtures thereof.
Selon un autre mode de réalisation préféré, ledit agent de réticulation est choisi dans le groupe comprenant les acrylates mult i-fonct ionnels comprenant notamment l'hexanediol diméthylacrylate ( HDDMA ) , l'éthylène glycol diméthylacrylate ( EGDMA ) , le butanediol diacrylate ( BDDA ) , , le poly (éthylène glycol) diacrylate ( PEGDA ) et les mélanges de ceux-ci .  According to another preferred embodiment, said crosslinking agent is chosen from the group comprising multi-functional acrylates including hexanediol dimethylacrylate (HDDMA), ethylene glycol dimethylacrylate (EGDMA), butanediol diacrylate (BDDA) ,, poly (ethylene glycol) diacrylate (PEGDA) and mixtures thereof.
Selon un mode de réalisation préféré, ledit agent de réticulation est présent à une concentration comprise entre 1% et 5% en masse, encore plus préfèrentiellement entre 1 et 3 % en masse, encore plus préfèrentiellement entre 1 et 2% en masse par rapport à la masse totale de la composition. According to a preferred embodiment, said crosslinking agent is present at a concentration of between 1% and 5% by weight, even more preferably between 1 and 3% by weight, still more preferably between 1 and 2% by weight relative to the total mass of the composition.
Selon un mode de réalisation préféré, ledit agent de réticulation est présent à une concentration comprise entre 0.1 et 3% en masse, encore plus préfèrentiellement entre 0.1 et 0.5 % en masse, encore plus préfèrentiellement entre 0.1 et 0.3% en masse et tout à fait préfèrentiellement à une concentration de 0.2% en masse par rapport à la masse totale de la composition.  According to a preferred embodiment, said crosslinking agent is present at a concentration of between 0.1 and 3% by weight, even more preferably between 0.1 and 0.5% by weight, still more preferably between 0.1 and 0.3% by weight and quite preferably at a concentration of 0.2% by weight relative to the total mass of the composition.
Selon un mode de réalisation préféré la composition selon l'invention comprend un photo-amorceur . L'homme du métier choisira en fonction du spectre d'émission de la lampe utilisée le photoamorceur le plus adapté.  According to a preferred embodiment, the composition according to the invention comprises a photoinitiator. The skilled person will choose according to the emission spectrum of the lamp used the most suitable photoinitiator.
Le photoamorceur peut être choisi parmi : 2,2- diméthoxyphényl-2-acétophénone (DMPA) camphorquinone ou 4, 4 '-bis (diethylamino ) enzophenone, cette liste étant non limitative .  The photoinitiator may be chosen from: 2,2-dimethoxyphenyl-2-acetophenone (DMPA) camphorquinone or 4,4'-bis (diethylamino) enzophenone, this list being non-limiting.
Avantageusement le photoamorceur est utilisé à une concentration comprise entre 0,2 et 1%, préfèrentiellement entre 0.2 et 0.3% en masse.  Advantageously, the photoinitiator is used at a concentration of between 0.2 and 1%, preferably between 0.2 and 0.3% by weight.
Selon un mode de réalisation préféré, ledit photo¬ amorceur est le DMPA. According to a preferred embodiment, said light ¬ initiator is DMPA.
Selon un mode de réalisation de l'invention, ladite composition comprend un solvant et encore plus préfèrentiellement ledit solvant est de l'eau. Selon un autre mode de réalisation préféré, ledit solvant est un alcool et tout à fait préfèrentiellement de l'éthanol.  According to one embodiment of the invention, said composition comprises a solvent and even more preferably said solvent is water. According to another preferred embodiment, said solvent is an alcohol and quite preferably ethanol.
Selon un autre mode de réalisation préféré, ladite composition est dépourvue de solvant.  According to another preferred embodiment, said composition is devoid of solvent.
Dans le cadre de la présente invention, le terme « comprend » entend signifier que la composition selon l'invention inclut les éléments cités. De manière préférée, la présente invention concerne des compositions comprenant uniquement les éléments cités à l'exclusion de tout autre. In the context of the present invention, the term "comprises" means that the composition according to the invention includes the elements mentioned. Preferably, the present invention relates to compositions comprising only the elements cited to the exclusion of any other.
La présente invention concerne également un procédé pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un matériau à un tissu biologique, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice (hémostase, aérostase) dans un tissu biologique, pour renforcer un tissu biologique et/ou pour fixer et stabiliser un tissu biologique, remarquable en ce qu'il comprend les étapes :  The present invention also relates to a method for the adhesion of biological tissues to one another, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or a substance to the surface of a tissue. biological, for closing an orifice (hemostasis, aerostasis) in a biological tissue, for strengthening a biological tissue and / or for setting and stabilizing a biological tissue, remarkable in that it comprises the steps:
-(i) enduire le tissu à traiter d'une composition selon invention,  (i) coating the fabric to be treated with a composition according to the invention,
-(ii) laisser pénétrer la composition dans ledit tissu, (ii) allowing the composition to penetrate into said tissue,
-(iii) induire, par rayonnement UV, la polymérisation de ladite composition. (iii) inducing, by UV radiation, the polymerization of said composition.
Le procédé selon l'invention est avantageusement non- invasif . Le terme « non-invasif » entend signifier que le procédé selon l'invention ne comprend aucune étape chirurgicale consistant à accéder au tissu à traiter. Ainsi, le procédé selon l'invention est mis en œuvre sur un tissu biologique directement accessible (e.g. la peau) ou préalablement rendu accessible par d'autres méthodes.  The method according to the invention is advantageously non-invasive. The term "non-invasive" means that the method according to the invention does not include any surgical step of accessing the tissue to be treated. Thus, the method according to the invention is implemented on a biological tissue directly accessible (e.g. the skin) or previously made accessible by other methods.
Les caractéristiques du rayonnement UV mis en œuvre, notamment sa puissance et sa longueur d'onde, sont adaptées aux constituants de la composition, notamment à la nature du monomère polymérisable et à sa concentration dans la composition .  The characteristics of the UV radiation used, in particular its power and its wavelength, are adapted to the constituents of the composition, in particular to the nature of the polymerizable monomer and to its concentration in the composition.
Selon un mode de réalisation préféré, ledit procédé comprend en outre après l'étape (iii), une étape (iv) consistant en l'apposition d'un tissu synthétique à la surface du tissu.  According to a preferred embodiment, said method further comprises after step (iii), a step (iv) of apposition of a synthetic fabric to the surface of the fabric.
Selon un mode de réalisation préféré, ledit rayonnement UV a une longueur d'onde comprise entre 150 et 280 nm. Selon un mode de réalisation préféré, ledit rayonnement UV a une puissance comprise entre 100 et 200 W. According to a preferred embodiment, said UV radiation has a wavelength of between 150 and 280 nm. According to a preferred embodiment, said UV radiation has a power of between 100 and 200 W.
La présente invention concerne également un ensemble de parties comprenant une composition selon l'invention et une source de rayonnement UV . De préférence la source de rayonnement UV de l'ensemble de parties peut émettre un rayonnement UV adapté pour polymériser et/ou aider la polymérisation et/ou accélérer la polymérisation du monomère polymérisable de la composition.  The present invention also relates to a set of parts comprising a composition according to the invention and a source of UV radiation. Preferably, the UV radiation source of the set of parts can emit UV radiation suitable for polymerizing and / or aiding the polymerization and / or accelerating the polymerization of the polymerizable monomer of the composition.
Dans le cadre de la présente invention, le terme In the context of the present invention, the term
« source de rayonnement UV » fait référence à tout moyen artificiel apte à produire un rayonnement UV et plus particulièrement un rayonnement de longueur d'onde comprise entre 150 et 280 nm encore plus préfèrentiellement entre 170 nm à 260 nm et tout à fait préfèrentiellement entre 190 nm et 240 nm. De manière préférée ledit rayonnement UV est de puissance comprise entre 0.5 W et 200W et tout à fait préfèrentiellement entre 100 et 200W. "UV radiation source" refers to any artificial means capable of producing UV radiation and more particularly a radiation of wavelength lying in the range 150 nm to 280 nm, even more preferably in the range 170 nm to 260 nm and most preferably in the range 190 nm to 260 nm. nm and 240 nm. Preferably said UV radiation is of power between 0.5 W and 200W and quite preferentially between 100 and 200W.
Selon un autre mode de réalisation préféré le terme « source de rayonnement UV » fait référence à tout moyen artificiel apte à produire un rayonnement UV d'une longueur d'onde comprise entre de 200 nm à 400 nm, encore plus préfèrentiellement entre 300 nm à 400 nm et tout à fait préfèrentiellement entre 350 nm et 400 nm.  According to another preferred embodiment, the term "UV radiation source" refers to any artificial means capable of producing UV radiation with a wavelength of between 200 nm and 400 nm, and even more preferably between 300 nm at 400 nm and quite preferably between 350 nm and 400 nm.
De manière tout à fait préférée, ledit rayonnement UV est de longueur d'onde comprise entre 150 et 280 nm et de puissance comprise entre 100 et 200W.  Most preferably, said UV radiation has a wavelength of between 150 and 280 nm and a power of between 100 and 200 W.
Description des modes de réalisation Description of the embodiments
Matériels et méthodes Materials and methods
Test de pelage Des solutions d'acide acrylique,Peel test Acrylic acid solutions,
(Hydroxyéthyl ) methacrylate/acide acrylique, (Hydroxypropyl ) methacrylate/acide acrylique, acide acrylique/acrylate de tert-butyle/agents de réticulation, méthacrylate/acide (Hydroxyethyl) methacrylate / acrylic acid, (Hydroxypropyl) methacrylate / acrylic acid, acrylic acid / tert-butyl acrylate / crosslinking agents, methacrylate / acid
acrylique/ (Hydroxyéthyl ) methacrylate/agents de réticulation, ou acide acrylique/ méthacrylate de diméthylaminoéthyle/agents de réticulation de viscosité et de concentrations variables ont été déposées sur des échantillons de péricardes bovins. Cette étape est réalisée à 20°C. Lesdits échantillons de péricarde ont été soumis à un rayonnement UV de 150 W, pendant une durée de 5 min., afin de déclencher la polymérisation des monomères. La source de rayonnement a été placée à 10 cm du péricarde. Acrylic / (Hydroxyethyl) methacrylate / crosslinking agents, or acrylic acid / dimethylaminoethyl methacrylate / crosslinking agents of viscosity and varying concentrations were deposited on bovine pericardial samples. This step is carried out at 20 ° C. These pericardial samples were subjected to 150 W UV radiation for a period of 5 minutes to initiate polymerization of the monomers. The radiation source was placed 10 cm from the pericardium.
Lesdits échantillons de péricarde ont été ensuite recouverts d'une bande de toile de verre, cette dernière a ensuite reçu une solution de monomères identique à celle utilisée à l'étape précédente.  These pericardial samples were then covered with a strip of glass cloth, the latter then receiving a solution of monomers identical to that used in the previous step.
Les échantillons de péricarde ont été soumis à un rayonnement UV dans des conditions identiques à celles de l'étape précédente.  The pericardial samples were subjected to UV radiation under conditions identical to those of the previous step.
Un test de pelage a ensuite été effectué par traction à 180° sur la bande de fibre de verre dans un four régulé à 37°C. Le temps de repos de la bande installée entre les mors de la machine de traction est d'une minute, la température au sein de l'échantillon est, au moment du lancement du test, de 30°C + ou - 4 °C.  A peel test was then performed by pulling 180 ° on the fiberglass strip in a controlled oven at 37 ° C. The rest time of the belt installed between the jaws of the traction machine is one minute, the temperature within the sample is, at the time of the test start, 30 ° C + or - 4 ° C.
Observation au Microscope électronique à balayage environnemental Environmental scanning electron microscope observation
Une solution d'acide acrylique a été déposée sur des échantillons de péricarde. Lesdits échantillons de péricarde ont été soumis à un rayonnement UV de 150 W, pendant 5 min., afin de déclencher la polymérisation des monomères. La source de rayonnement a été placée à 10 cm du péricarde. A solution of acrylic acid was deposited on pericardial samples. Said pericardial samples were subjected to 150 W UV radiation for 5 min., to trigger the polymerization of the monomers. The radiation source was placed 10 cm from the pericardium.
Les échantillons de péricarde ont ensuite été coupés transversalement et observés par microscopie électronique à balayage .  The pericardial samples were then cut transversely and observed by scanning electron microscopy.
Résultats Results
Test de pelage Peel test
Les résultats obtenus sont présentés dans le tableau ci-dessous .  The results obtained are shown in the table below.
Sur tous les essais effectués, on observe, quel que soit l'adhésif utilisé, un taux d'environ 70% de rupture dans le tissu ou la bande de fibres de verre et 30% dans l'adhésif. Quand la rupture a lieu dans l'adhésif, la force nécessaire pour détruire l'assemblage est équivalente à celle obtenue pour une rupture dans la fibre de verre.  In all the tests carried out, there is observed, regardless of the adhesive used, a rate of about 70% of rupture in the fabric or the strip of glass fibers and 30% in the adhesive. When the break occurs in the adhesive, the force needed to destroy the assembly is equivalent to that obtained for a break in the fiberglass.
On observe que la résistance à la rupture (i.e. la résistance du collage) croît inversement à la viscosité, de la composition selon l'invention, utilisée.  It is observed that the breaking strength (i.e. the resistance of the bonding) increases inversely with the viscosity of the composition according to the invention used.
Tableau 1 Table 1
Composition utilisée (toutes Viscosité [mPa.s] Résistance à la rupture F/b les compositions comprennent [N/m] dans le péricarde 0.25% en masse de DMPA)  Composition used (all Viscosity [mPa.s] Resistance to rupture F / b the compositions comprise [N / m] in the pericardium 0.25% by weight of DMPA)
100% acide acrylique 1 300  100% acrylic acid 1,300
25%HEMA 75%AA 3 300  25% HEMA 75% AA 3,300
50% HEM A 50%AA 4 250  50% HEM A 50% AA 4,250
75%HEMA 25%AA 6 200  75% HEMA 25% AA 6,200
25%HPMA 75%AA 3 400  25% HPMA 75% AA 3 400
50%HPMA 50%AA 4.5 300  50% HPMA 50% AA 4.5 300
75%HPMA 25%AA 6.5 100  75% HPMA 25% AA 6.5 100
65% AA 35% tBuAC 1.23 400  65% AA 35% tBuAC 1.23 400
2%HDDMA 2% HDDMA
50% AA 50% tBuAC 1.23 190  50% AA 50% tBuAC 1.23 190
2%HDDMA 50% AA 25% HEMA 25% MA 1.81 190 2% HDDMA 50% AA 25% HEMA 25% MA 1.81 190
2%HDDMA 2% HDDMA
90% AA 10% DMAEMA 9.6 322  90% AA 10% DMAEMA 9.6 322
2%HDDMA 2% HDDMA
65% AA 35% tBuAC 1.18 343  65% AA 35% tBuAC 1.18 343
2%EGDMA 2% EGDMA
65% AA 35% tBuAC 2%BDDA 1.27 286  65% AA 35% tBuAC 2% BDDA 1.27 286
65% AA 35% tBuAC 1.5 382 65% AA 35% tBuAC 1.5 382
2%PEGDA 2% PEGDA
Observation au Microscope électronique à balayage Observation with Scanning Electron Microscope
On observe la présence du polymère formé infiltré dans la surface du tissu sur une profondeur de 50pm. On observe par ailleurs que le polymère formé a pénétré dans les espaces entre les fibres de collagène des tissus.  The presence of the formed polymer infiltrated in the surface of the fabric is observed at a depth of 50 μm. It is furthermore observed that the polymer formed has penetrated into the spaces between the collagen fibers of the tissues.
Cette observation indique la capacité des compositions selon l'invention à pénétrer dans les tissus ce qui explique la parfaite adhésion obtenue.  This observation indicates the ability of the compositions according to the invention to penetrate the tissues which explains the perfect adhesion obtained.

Claims

REVENDICATIONS
1 - Composition, destinée à être utilisée dans un procédé pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un matériau à un tissu biologique, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice dans un tissu biologique, pour renforcer un tissu biologique et/ou pour fixer et stabiliser un tissu biologique caractérisée en ce qu'elle comprend un monomère polymérisable sous l'effet d'un rayonnement ultra-violet (UV) et en ce que sa viscosité est inférieure à 10 mPa.s à 20°C. 1 - Composition, intended to be used in a process for the adhesion of biological tissues to one another, for the adhesion of a material to a biological tissue, for the adhesion of an adhesive or a substance to the surface biological tissue, for closing an orifice in a biological tissue, for reinforcing a biological tissue and / or for fixing and stabilizing a biological tissue characterized in that it comprises a polymerizable monomer under the effect of ultra-violet radiation. violet (UV) and in that its viscosity is less than 10 mPa.s at 20 ° C.
2 - Composition selon la revendication précédente, caractérisée en ce que ledit rayonnement UV a une longueur d'onde comprise entre de 150 nm à 280 nm, encore plus préfèrentiellement entre 170 nm à 260 nm et tout à fait préfèrentiellement entre 190 nm et 240 nm. 2 - Composition according to the preceding claim, characterized in that said UV radiation has a wavelength between 150 nm to 280 nm, even more preferably between 170 nm to 260 nm and quite preferably between 190 nm and 240 nm .
3 - Composition selon l'une des revendications précédentes, caractérisée en ce que le monomère polymérisable est uniquement polymérisable par irradiation par rayonnements UV. 3 - Composition according to one of the preceding claims, characterized in that the polymerizable monomer is only polymerizable by irradiation with UV radiation.
4 - Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle ne comprend pas de monomères polymérisables dont la polymérisation peut être initiée au seul contact de molécules d'eau. 4 - Composition according to one of the preceding claims, characterized in that it does not comprise polymerizable monomers whose polymerization can be initiated at the single contact with water molecules.
5 - Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle ne comprend pas de monomères polymérisables de la famille des cyanoacrylates . 6 - Composition selon une des revendications 1 à 5, caractérisée en ce que sa viscosité est inférieure à 6 mPa.s à 20°C. 5 - Composition according to one of the preceding claims, characterized in that it does not include polymerizable monomers of the cyanoacrylate family. 6 - Composition according to one of claims 1 to 5, characterized in that its viscosity is less than 6 mPa.s at 20 ° C.
7 - Composition selon la revendication précédente, caractérisée en ce que sa viscosité est inférieure à 2 mPa.s à 20°C. 8 - Composition selon l'une des revendications précédentes, caractérisée en ce que ledit monomère est un monomère d'acrylate ou de méthacrylate ou un oligomère d'acrylate ou de méthacrylate. 9 - Composition selon l'une des revendications précédentes, caractérisée en ce que ledit monomère comprend une fonction polaire. 7 - Composition according to the preceding claim, characterized in that its viscosity is less than 2 mPa.s at 20 ° C. 8 - Composition according to one of the preceding claims, characterized in that said monomer is an acrylate or methacrylate monomer or an acrylate oligomer or methacrylate. 9 - Composition according to one of the preceding claims, characterized in that said monomer comprises a polar function.
10 - Composition selon la revendication précédente, caractérisée en ce que ladite fonction polaire est choisie dans le groupe comprenant les fonctions hydroxyle, amide, carboxyle, amino, carbonate, carbamate, sulfonamide, sulfonique, phosphonique, méthoxyéthyle, méthoxyéthoxyéthyle, hydroxyéthyle et hydroxyéthoxyéthyle . 10 - Composition according to the preceding claim, characterized in that said polar function is selected from the group comprising hydroxyl, amide, carboxyl, amino, carbonate, carbamate, sulfonamide, sulfonic, phosphonic, methoxyethyl, methoxyethoxyethyl, hydroxyethyl and hydroxyethoxyethyl functions.
11 - Composition selon la revendication 9, caractérisée en ce que ledit monomère est choisi dans le groupe comprenant les mono-, di-, tri-, tetra- et penta-acrylates ou méthacrylates , et leurs mélanges. 11 - Composition according to claim 9, characterized in that said monomer is selected from the group consisting of mono-, di-, tri-, tetra- and penta-acrylates or methacrylates, and mixtures thereof.
12 - Composition selon la revendication 8 ou 11, caractérisée en ce que ledit monomère d'acrylate est choisi dans le groupe comprenant l'acide acrylique, le méthacrylate de méthyle; le méthacrylate de diméthylaminoéthyle ;l'acrylate d'éthyle; le méthacrylate de cyclohexyle ; le méthacrylate de 2-hydroxyethyle ; l'acrylate de 3-hydroxypropyle ; l'acrylate d ' alpha-bromoéthyle ; l'acrylate d ' alpha-chloroéthyle ; le méthacrylate de chlorométhyle ; le méthacrylate de 2-bromoéthyle ; le méthacrylate de 2-naphtyle; l'acrylate de paratolyle; le méthacrylate de parachlorophényle ; l'acrylate de metabromophényle ; l'acrylate de 2 , 4 , 6-tribromophényle ; le méthacrylate de parachlorobenzyle ; le méthacrylate de metaméthoxybenzyle ; l'acrylate de paraéthylbenzyle ; le di méthacrylate de 1 , 6-hexanediol ; le di acrylate de neopentylglycol; le di méthacrylate de thiodiéthylène-glycol ; le di acrylate de bisphénol A éthoxyle; le di méthacrylate de bisphénol A éthoxyle; le triacrylate de pentaérythritol ; le triacrylate de glycéryle; le pentaacrylate de dipentaérythritol ; le triacrylate de triméthylolpropane ; le tri méthacrylate de 1 ' isocyanurate de tris ( 2-hydroxyéthyle ) ; le triacrylate de triméthylolpropane polyoxyéthylène ; un acrylate d'uréthane; un methacrylate d'uréthane; le sulfure de bis ( 4-methacryloylthiophényle ) ; un éthylèneglycol ou un polyéthylèneglycol choisi dans le groupe constitué par l'acrylate, le methacrylate; le diacrylate, le dimethacrylate, et leurs mélanges. 12 - Composition according to claim 8 or 11, characterized in that said acrylate monomer is chosen from the group comprising acrylic acid, methacrylate methyl; dimethylaminoethyl methacrylate, ethyl acrylate; cyclohexyl methacrylate; 2-hydroxyethyl methacrylate; 3-hydroxypropyl acrylate; alpha-bromoethyl acrylate; alpha-chloroethyl acrylate; chloromethyl methacrylate; 2-bromoethyl methacrylate; 2-naphthyl methacrylate; paratolyl acrylate; parachlorophenyl methacrylate; metabromophenyl acrylate; 2,4,6-tribromophenyl acrylate; parachlorobenzyl methacrylate; metamethoxybenzyl methacrylate; paraethylbenzyl acrylate; 1,6-hexanediol di methacrylate; neopentyl glycol diacrylate; thiodiethylene glycol di methacrylate; ethoxylated bisphenol A diacrylate; ethoxylated bisphenol A di methacrylate; pentaerythritol triacrylate; glyceryl triacrylate; dipentaerythritol pentaacrylate; trimethylolpropane triacrylate; tri-methacrylate of tris (2-hydroxyethyl) isocyanurate; trimethylolpropane triacrylate polyoxyethylene; a urethane acrylate; urethane methacrylate; bis (4-methacryloylthiophenyl) sulfide; an ethylene glycol or a polyethylene glycol selected from the group consisting of acrylate, methacrylate; diacrylate, dimethacrylate, and mixtures thereof.
13 - Composition selon la revendication 8 ou 11, caractérisée en ce que ledit monomère d' acrylate est choisi dans le groupe comprenant 1 ' Hydroxyéthyl ) methacrylate, l'acide acrylique, 1 'Hydroxy (propyl) methacrylate, l'acrylate de tert-butyle, le méthacrylate de diméthylaminoéthyle et leurs mélanges. 14 - Composition selon l'une des revendications précédentes, caractérisée en ce que ledit monomère a une masse molaire comprise entre 50 et 300g. mol-1. 15 - Composition selon l'une des revendications précédentes caractérisée en ce qu'elle est dépourvue de solvant . 13 - Composition according to claim 8 or 11, characterized in that said acrylate monomer is selected from the group comprising 1 'hydroxyethyl) methacrylate, acrylic acid, 1 hydroxypropyl methacrylate, acrylate tert- butyl, dimethylaminoethyl methacrylate and mixtures thereof. 14 - Composition according to one of the preceding claims, characterized in that said monomer has a molar mass of between 50 and 300g. mol -1 . 15 - Composition according to one of the preceding claims characterized in that it is devoid of solvent.
16 - Composition selon l'une des revendications précédentes, caractérisée en ce que ledit monomère a une concentration comprise entre 90 et 100% en masse par rapport à la masse totale de la composition. 16 - Composition according to one of the preceding claims, characterized in that said monomer has a concentration of between 90 and 100% by weight relative to the total mass of the composition.
17 - Composition selon l'une des revendications précédentes caractérisée en ce qu'elle comprend en outre un agent de réticulation. 17 - Composition according to one of the preceding claims characterized in that it further comprises a crosslinking agent.
18 - Composition selon la revendication précédente caractérisée en ce que ledit agent de réticulation comprend une fonction acrylate. 18 - Composition according to the preceding claim characterized in that said crosslinking agent comprises an acrylate function.
19 - Composition selon la revendication précédente, caractérisée en ce que ledit agent de réticulation est choisi dans le groupe comprenant les acrylates multi-fonctionnels comprenant notamment le 1 , 6-hexanediol di acrylate, l'hexanediol diméthylacrylate (HDDMA) , l'éthylène glycol diméthylacrylate (EGDMA) , le butanediol diacrylate (BDDA) , le triméthylolpropane tri acrylate, le 1,2-éthylène glycol di acrylate, le poly (éthylène glycol) diacrylate (PEGDA) , le pentaérythritol tétracrylate et les mélanges de ceux-ci. 19 - Composition according to the preceding claim, characterized in that said crosslinking agent is selected from the group comprising multifunctional acrylates comprising in particular 1,6-hexanediol di acrylate, hexanediol dimethyl acrylate (HDDMA), ethylene glycol dimethylacrylate (EGDMA), butanediol diacrylate (BDDA), trimethylolpropane tri acrylate, 1,2-ethylene glycol diacrylate, poly (ethylene glycol) diacrylate (PEGDA), pentaerythritol tetracrylate and mixtures thereof.
20 - Composition selon l'une des revendications 17 à 19, caractérisée en ce que ledit agent de réticulation est présent à une concentration comprise entre 1% et 5% en masse, encore plus préfèrentiellement entre 1 et 3 % en masse, encore plus préfèrentiellement entre 1 et 2% en masse par rapport à la masse totale de la composition. 20 - Composition according to one of claims 17 to 19, characterized in that said crosslinking agent is present at a concentration of between 1% and 5% by weight, more preferably between 1 and 3% by weight, even more preferably between 1 and 2% by weight relative to the total mass of the composition.
21 - Composition selon l'une des revendications 1 à 20, caractérisée en ce qu'elle comprend en outre un photo- amorceur .  21 - Composition according to one of claims 1 to 20, characterized in that it further comprises a photoinitiator.
22 - Composition selon la revendication 21, caractérisée en ce que ledit photo-amorceur est choisi dans le groupe comprenant le 2 , 2-diméthoxyphényl-2-acétophénone (DMPA) , la camphorquinone et le 4,4'- bis (diethylamino ) benzophenone . 23 - Composition selon l'une des revendications 21 à22 - Composition according to claim 21, characterized in that said photoinitiator is selected from the group comprising 2, 2-dimethoxyphenyl-2-acetophenone (DMPA), camphorquinone and 4,4'-bis (diethylamino) benzophenone . 23 - Composition according to one of claims 21 to
22, caractérisée en ce que ledit photo-amorceur est à une concentration comprise entre 0,2 et 1%, préfèrentiellement entre 0.2 et 0.3% en masse. 24 - Procédé, non-invasif, pour l'adhésion de tissus biologiques entre eux, pour l'adhésion d'un tissu biologique à un matériau, pour l'adhésion d'une colle ou d'une substance à la surface d'un tissu biologique, pour obturer un orifice dans un tissu biologique, pour renforcer un tissu biologique et/ou pour fixer et stabiliser un tissu biologique caractérisé en ce qu'il comprend les étapes : 22, characterized in that said photoinitiator is at a concentration of between 0.2 and 1%, preferably between 0.2 and 0.3% by weight. 24 - Method, non-invasive, for the adhesion of biological tissues to one another, for the adhesion of a biological tissue to a material, for the adhesion of an adhesive or a substance to the surface of a biological tissue, for closing an orifice in a biological tissue, for strengthening a biological tissue and / or for fixing and stabilizing a biological tissue, characterized in that it comprises the steps of:
-(i) enduire le tissu à traiter d'une composition selon l'une des revendications 1 à 23, (i) coating the fabric to be treated with a composition according to one of claims 1 to 23,
-(ii) laisser pénétrer la composition dans ledit tissu, -(iii) induire, par rayonnement UV, la polymérisation de ladite composition. 25 - Procédé selon la revendication précédente caractérisé en ce qu'il comprend en outre, après l'étape (iii), une étape (iv) consistant en l'apposition d'un tissu synthétique à la surface dudit tissu. - (ii) permitting the composition to penetrate into said tissue; (iii) inducing, by UV radiation, the polymerization of said composition. 25 - Method according to the preceding claim characterized in that it further comprises, after step (iii), a step (iv) consisting of the apposition of a synthetic fabric to the surface of said fabric.
26 - Procédé selon la revendication 24 caractérisé en ce que ledit rayonnement UV a une longueur d'onde comprise entre 150 et 280 nm. 27 - Procédé selon l'une des revendications 24 à 26 caractérisé en ce que ledit rayonnement UV a une puissance comprise entre 100 et 200W. 26 - The method of claim 24 characterized in that said UV radiation has a wavelength between 150 and 280 nm. 27 - Method according to one of claims 24 to 26 characterized in that said UV radiation has a power between 100 and 200W.
28 - Ensemble de parties comprenant une composition selon l'une des revendications 1 à 23 et une source de rayonnement UV. 28 - Set of parts comprising a composition according to one of claims 1 to 23 and a source of UV radiation.
EP16732691.7A 2015-05-21 2016-05-20 Surgical adhesives Active EP3297692B1 (en)

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FR1554583A FR3036288B1 (en) 2015-05-21 2015-05-21 SURGICAL GLUES
PCT/FR2016/051211 WO2016185153A1 (en) 2015-05-21 2016-05-20 Surgical adhesives

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CN113350564B (en) * 2021-05-20 2023-03-10 诺一迈尔(苏州)生命科技有限公司 Biodegradable tissue adhesive patch and preparation method thereof
WO2023156749A1 (en) 2022-02-18 2023-08-24 Cohesives Photopolymerisable composition for adhesive for biological tissue

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FR3036288A1 (en) 2016-11-25
US11207443B2 (en) 2021-12-28
CA2986308A1 (en) 2016-11-24
JP2018517477A (en) 2018-07-05
FR3036288B1 (en) 2018-10-26
JP7019884B2 (en) 2022-02-16
US20220143264A1 (en) 2022-05-12
ES2908874T3 (en) 2022-05-04
AU2016263552A1 (en) 2018-01-04
EP3297692B1 (en) 2022-01-05
WO2016185153A1 (en) 2016-11-24
CN107771086A (en) 2018-03-06
CN107771086B (en) 2021-11-05
US20180280564A1 (en) 2018-10-04

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